Female Reproductive Disorders F23 D2L.pdf

Female Reproductive Disorders Beth Zerr, PharmD BCACP 11/28/23 Abbreviations • E – estrogen • P – progesterone / progestin • BTB – break-through bleeding • PCOS – polycystic ovary syndrome • FSH – follicle stimulating hormone • LH – luteinizing hormone • GnRH – gonadotropin releasing hormone • H...

Female Reproductive Disorders Beth Zerr, PharmD BCACP 11/28/23 Abbreviations • E – estrogen • P – progesterone / progestin • BTB – break-through bleeding • PCOS – polycystic ovary syndrome • FSH – follicle stimulating hormone • LH – luteinizing hormone • GnRH – gonadotropin releasing hormone • HPA – hypothalamus pituitary adrenal axis • T – testosterone • DHT – dihydrotestosterone • hCG - human chorionic gonadotropin • hCS - human chorionic somatotropin • CHC – combination hormonal contraceptives • PID – pelvic inflammatory disorder Female reproductive disorders - Introduction Timing • Reproductive years • Altered menstruation • Pelvic pain • Infertility • Late reproductive years and menopause • Cancers • High mortality rates and high incidences of metastases • Due to difficulty detecting • There is one exception … Affected organs/systems • Arise in reproductive organs • Arise in non-reproductive organs • Affect non-reproductive organs Female reproductive disorders - Introduction Timing • Reproductive years • Altered menstruation • Pelvic pain • Infertility • Late reproductive years and menopause • Cancers • High mortality rates and high incidences of metastases • Due to difficulty detecting • There is one exception … Ovaries, fallopian tubes, uterus, cervix, vagina, breast Brain, hypothalamus, pituitary, thyroid, adrenals, kidney, liver Affected organs/systems • Arise in reproductive organs • Arise in non-reproductive organs • Affect non-reproductive organs Osteoporosis, atherogenesis, gestational diabetes Outline • Normal structure and function • Pathophysiology of menstrual disorders • Pathophysiology of infertility • Pathophysiology of common disorders of pregnancy Differentiation of male and female reproductive organs • Males • Wolffian duct • Sertoli cells → anti-mullerian hormone • Leydig cells → testosterone • DHT • Females • Mullerian duct • Absence of anti-mullerian hormone, testosterone and DHT • Estrogen Citation: Chapter 9 Reproductive Physiology, kibble JD. The Big Picture Physiology: Medical Course & Step 1 Review, 2e; 2020. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=24554 4542&gbosContainerID=0&gbosid=0&groupID=0&sectionId=245544 538&multimediaId=undefined Accessed: April 12, 2021 Copyright © 2021 McGraw-Hill Education. All rights reserved Normal structure and function Reproductive pelvic organs Discussion questions 1. Functions during non-pregnant state vs pregnancy? 2. When do eggs develop? 3. How many eggs does a female have? How many are released during her lifetime? Anatomic landmarks of the uterus and adjacent organs. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.) Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Normal Structure and Function Breast Non-pregnant During Pregnancy After Pregnancy Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Normal Structure and Function Menstruation • Monthly cycle to prepare for reproduction • Follicular phase, Ovulation, Luteal phase • FSH, LH, estradiol, and progesterone • To understand the menstrual cycle → understand the interplay between • • • • Ovaries Pituitary hormones Ovarian hormones Uterus / endometrial lining Normal Structure and Function Ovaries Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Normal Structure and Function Hormones GnRH Inhibin Negative feedback on FSH https://www.google.com/url?sa=i&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiv0Jnq_dfhAhWZFjQIHdmDDSgQjRx6BAgBEAU&url=https%3A%2F%2Fslideplayer.com%2Fslide%2F6406554%2F&psig=AOvVa w3RCKuCfP5XCDKofo4x3rvB&ust=1555619881470026 Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased during the neonatal years but go through a period of childhood quiescence before increasing again during puberty. Gonadotropin levels are cyclic during the reproductive years and increase dramatically with the loss of negative feedback that accompanies menopause. Citation: Disorders of the Female Reproductive System, Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, 20e; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=192287740&bookid=2129&Resultclick=2 Accessed: April 21, 2020 Copyright © 2020 McGraw-Hill Education. All rights reserved Estrogen production requires both FSH and LH Two cell model for steroidogenesis LH – brings cholesterol into the theca cell FSH – stimulates aromatization of androstenedione and testosterone to estrogen in granulosa cell Estrogen production in the ovary requires the cooperative function of the theca and granulosa cells under the control of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). HSD, hydroxysteroid dehydrogenase; OHP, hydroxyprogesterone. Citation: Disorders of the Female Reproductive System, Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, 20e; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=192287740&bookid=2129&Resultclick=2 Accessed: April 21, 2020 Copyright © 2020 McGraw-Hill Education. All rights reserved Copyrights apply Estrogen and Progesterone action • Both • Expression of secondary sexual characteristics • Estrogen • Development of ductal system of the breasts • Create receptive environment for pregnancy and parturition • Progesterone • Development of glandular system of the breasts • Increases basal body temperature (clinical marker of ovulation) • Inhibits uterine contractions Fill in the blank – hormone review 1 2 The brain induces the hypothalamus to release GnRH into the portal circulation of the pituitary in a 3pulsatile fashion. Releasing this hormone in a4pulsatile fashion is critical to properly activate receptors located on the pituitary gland. The pituitary gland then releases5FSH and6LH, which act on the ovaries, stimulating the production of 10 7 estrogen and 8inhibin. Negative feedback from9inhibin suppresses FSH secretion but has no effect on11LH. Estrogen production by the ovaries 13 will then induce a12mid-cycle LH surge which induces ovulation. Estrogen also increases the number of14GnRH receptors and sensitivity to15GnRH by the pituitary. The16corpus luteum produces high levels of 17 progesterone which then suppresses FHS and LH for the remainder of the luteal phase. Normal Structure and Function Conception 1. Ovulation 2. Mature oocyte moves into fallopian tubes 3. Fertilization via viable sperm 4. Implantation Normal Structure and Function Pregnancy Placenta Hormones released by the placenta Hormone production • hCG • Progesterone • hCS hCG supports the corpus luteum to remain viable until the placenta is able to produce P Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Normal Structure and Function Pregnancy Lactation Summary Pregnancy • Milk production stimulated via prolactin, progesterone and hCS • Milk release blocked via placental steroids (E and P) Soon after delivery • Estrogen and progesterone fall dramatically Lactation • Prolactin maintains milk production • Oxytocin causes milk release Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Normal structure and function Menopause • Exhaustion of supply of functioning ovarian follicles • Menstrual cycles cease • Menopause definition – 1 year AFTER last menstrual cycle • Transition / perimenopause • Estrogen levels decrease – causing FSH to increase • Symptoms associated with menopause • Vasomotor / systemic • Vulvovaginal • Atrophy of estrogen-dependent tissue • Gradual loss in bone density Normal structure and function Menopause Summary • Normal structure and function • Ovaries, fallopian tubes, uterus, cervix, vagina, breast • Estrogen formation and action in the body • Menstrual cycle • FSH, LH, estradiol, and progesterone • Ovaries and egg life cycle • Pregnancy • Placental hormones • Lactation – oxytocin and prolactin • Menopause • Pathophysiology of menstrual disorders • Pathophysiology of infertility • Pathophysiology of common disorders of pregnancy Pathophysiology Menstrual disorders Amenorrhea • Primary or secondary • Causes 1) Natural 2) Uterine • Often after curettage 3) Ovarian • Primary • ↑ FSH/LH and ↓ E • Secondary • Growing follicles result in ↑E, but never mature and ovulate 4) HPA disorders Pathophysiology Menstrual disorders Amenorrhea • HPA disorders • • • • • • Thyroid dysfunction Hyperprolactinemia Lactation Meds – 2nd gen antipsychotics Functional hypothalamic amenorrhea PCOS Pathophysiology Menstrual disorders – Polycystic Ovary Syndrome Insulin resistance (skeletal muscle and liver) Elevated serum insulin Ovaries remain sensitive to insulin Androgen production is induced Androgen excess Androgen excess s/s = hirsutism, acne, anovulation, irregular menses, male pattern hair loss Pathophysiology Menstrual disorders – Polycystic Ovary Syndrome Key points • • • • Common – 4-12% of women in the US Insulin resistance and ↑ insulin levels Increased androgens Amenorrhea likely due to anovulation • Infertility • Cancer • Treatment • Lifestyle changes • Combination estrogen/progestin contraceptives • Spironolactone • Clomiphene • (Metformin – no longer recommended by ACOG) Infertility Endometrial cancer →Arrest in follicle development →Polycystic ovaries →Anovulation →Lack of progestin due to anovulation and no formation of corpus luteum →Unopposed estrogen (BTB possible) →Unchecked endometrial growth Pathophysiology Menstrual disorders Dysmenorrhea • Primary vs secondary • Primary • Disordered prostaglandin production via endometrium • Prostaglandin F2α – myometrial contractions → PAIN - oversupply • Prostaglandin E’s – inhibit contractions • Secondary • Endometriosis Pathophysiology Menstrual disorders – Endometriosis Key points • • • • • • Endometrium outside of the uterus 1/10 women Implant sites respond to estrogen and progesterone same as endometrium in uterus Adhesions and inflammation = infertility risk and pain Diagnosis via laparoscopy Treatment • Pain meds - NSAIDs • Hormonal medications • Combination estrogen/progestin contraceptives • Progestin only contraceptives • GnRH agonists/antagonists • Surgery – local or hysterectomy Pathophysiology Menstrual disorders Abnormal Menstrual Bleeding (menorrhagia) • Bleeding that is not at the right time or is too heavy • PALM-COEIN • • • • • • • • • (uterine) Polyps Adenomyosis Leiomyoma Malignancy Coagulopathy Ovulatory dysfunction Endometrial Iatrogenic Not yet classified Summary • Normal structure and function • Pathophysiology of menstrual disorders • Amenorrhea • Natural, uterine, ovarian (primary vs secondary), HPA • PCOS • Dysmenorrhea • Primary vs secondary • Endometriosis • Abnormal menstrual bleeding • PALM-COEIN • Pathophysiology of infertility • Pathophysiology of common disorders of pregnancy Pathophysiology Infertility 1 2 3 Pathophysiology Infertility – Ovulatory causes • Originating in the hypothalamus or pituitary • Via inadequate gonadotropic stimulation … not enough FSH and LH • Originating in the ovaries • Failure of follicle to mature and ovulate • Diminished ovarian reserve • Other • PCOS • Treatment • Exogenous FHS and LH administration • Clomiphene Inhibin Pathophysiology Infertility – Tubal/Pelvic and Other causes Pelvic and Tubal • Normal follicles and hormone function • Abnormality in the endometrium or fallopian tubes • Pelvic Inflammatory Disorder • Prior or ongoing pelvic infections • Endometriosis Other • Hypothyroidism • Hyperprolactinemia Summary • Normal structure and function • Pathophysiology of menstrual disorders • Pathophysiology of infertility • Ovulatory (diminished ovarian reserve and PCOS) • Tubal (PID and endometriosis) • Others (hypothyroidism and hyperprolactinemia) • Pathophysiology of common disorders of pregnancy Normal pregnancy Gestational diabetes Common d/o’s of pregnancy Hyperglycemia (to meet fetal demands) Hyperglycemia (to meet fetal demands) • Gestational diabetes Increased maternal insulin Increased maternal insulin Intact insulin sensitivity Insulin resistance via hCS, P, cortisol Maternal serum glucose is normal Maternal serum glucose remains elevated Pathophysiology • ↑hCS, P, cortisol and prolactin all lead to relative insulin resistance • Higher risk for developing type II diabetes • Macrosomia Fetus receives adequate glucose Normal fetal growth Fetus receives elevated blood glucose Fetal pancreas releases more insulin Increased fetal growth Pathophysiology Common d/o’s of pregnancy • Miscarriage • Spontaneous abortion of pregnancy prior to when extrauterine life is possible • 20- 24 weeks gestation and 750 g body weight • Approximately 15% of pregnancies spontaneously terminate in the first trimester due to genetic malformations • Complications • Hemorrhage • May necessitate transfusion or surgical evacuation • Infection • Incidence increases with gestational age at pregnancy loss • May require emergency evaluation Pathophysiology Common d/o’s of pregnancy • Ectopic pregnancy • Implantation in lining of fallopian tube • Damaged or scarred fallopian tubes can increase risk • Potentially life-threatening to mother Pathophysiology Common d/o’s of pregnancy Placental disorders • Placenta previa • Placental abruption Pathophysiology Common d/o’s of pregnancy Gestational hypertension • HTN after week 20 • Treated if BP > 160/110 Preeclampsia/eclampsia • Hypertension AND proteinuria OR other signs of end organ damage • 5% of pregnancies in US • Eclampsia - maternal seizure • Pathophysiology • Placental dysfunction – relative placental ischemia IUGR Pedal Edema Summary • Normal structure and function • Pathophysiology of menstrual disorders • Pathophysiology of infertility • Pathophysiology of common disorders of pregnancy • • • • Gestational diabetes Ectopic pregnancy Placental disorders Gestational hypertension vs pre-eclampsia/eclampsia • Normal structure and function • Ovaries, fallopian tubes, uterus, cervix, vagina, breast • Estrogen formation and action in the body • Menstrual cycle • • FSH, LH, estradiol and progesterone Ovaries and egg life cycle • Pregnancy • • Placental hormones Lactation – oxytocin and prolactin • Menopause • Pathophysiology of menstrual disorders • Amenorrhea • • Natural, uterine, ovarian (primary vs secondary), HPA PCOS • Dysmenorrhea • • Primary vs secondary Endometriosis • Abnormal menstrual bleeding • PALM-COEIN • Pathophysiology of infertility • Ovulatory (diminished ovarian reserve and PCOS) • Tubal (PID and endometriosis) • Others (hypothyroidism and hyperprolactinemia) • Pathophysiology of common disorders of pregnancy • • • • Gestational diabetes Ectopic pregnancy Placental disorders Gestational hypertension vs pre-eclampsia/eclampsia Questions? Email Dr. Zerr at [email protected]